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Biomedical subjects

N Feller

Publications and source records attributed to N Feller.

At least 19 recordsLinked to original sources
PubMed1992

Probing daunorubicin accumulation defects in non-P-glycoprotein expressing multidrug-resistant cell lines using digitonin.

Multidrug resistance (MDR) in tumor cells is frequently associated with reduced cellular cytostatic drug accumulation, caused by the drug efflux protein, P-glycoprotein (Pgp). The action of Pgp in tumor cells can be detected by measuring the increase of daunorubicin accumulation upon blocking Pgp with drugs such as verapamil. A number of MDR cell lines have been described, characterized by decreased drug accumulation without Pgp being present. For such non-Pgp MDR cells no gene probes or functional assays are available to study this phenotype in clinical tumor specimens. We have worked out a method which enables the detection of drug-transport-related decreases in cellular daunorubicin accumulations without the need for the use of specific Pgp blockers. The cells used were SW-1573-, GLC4- and HT1080-sensitive cell lines, which accumulated (corrected for DNA content) 272%, 1,288% and 203% more daunorubicin than the non-Pgp MDR sublines SW-1573/2R120, GLC4/ADR and HT1080/DR4. When the plasma membranes of these MDR lines were permeabilized with 20 microM digitonin an increase to 282%, 1,260% and 239% of 14C-daunorubicin control accumulation was measured (at pH = 7.35). The intracellular pH measured with BCECF was the same in parent and corresponding MDR cells, excluding the role of pH differences in the measured effects. This method provides a tool allowing the detection of cellular mechanisms (including Pgp) which are related to active outward transport of daunorubicin.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Energy-dependent processes involved in reduced drug accumulation in multidrug-resistant human lung cancer cell lines without P-glycoprotein expression.

Mechanisms contributing to reduced cytotoxic drug accumulation were studied in two multidrug-resistant (MDR) human lung cancer cell lines without P-glycoprotein expression. In these (non-small cell) SW-1573/2R120 and (small cell) GLC4/ADR MDR cells, the steady-state accumulation of [14C]daunorubicin was 30 and 12%, respectively, of that in the parent cells. When cells, at steady state, were permeabilized with digitonin, the amount of daunorubicin binding increased only in the resistant cells. The reduced accumulation of daunorubicin in the SW-1573/2R120 and GLC4/ADR cells was accompanied by a lower initial (2 min) uptake rate of this drug. No difference in initial efflux rate of daunorubicin from preloaded cells could be detected between sensitive and resistant SW-1573 cells. However, daunorubicin was extruded 5-fold faster from GLC4/ADR cells than from the parental cells. In the presence of the energy metabolism inhibitors sodium azide and deoxyglucose, the reduced daunorubicin accumulations in the SW-1573/2R120 and GLC4/ADR MDR cells were (almost) completely reversed. The effects of these inhibitors on drug uptake were already apparent during the earliest measured time points (less than 15 s). Also, the enhanced efflux of daunorubicin from GLC4/ADR cells was inhibited. In ATP-depleted cells, the intracellular pH was lowered by approximately 0.3 units in resistant as well as in sensitive cells. The lower intracellular pH, however, could not account for the increase in daunorubicin accumulation in the resistant cells. Also, for vincristine and etoposide, the increases in drug accumulation under energy-deprived conditions were more pronounced in the resistant SW-1573/2R120 cells than in the parent SW-1573 cells. These results suggest that accumulation of drugs in the non-P-glycoprotein MDR human lung carcinoma cell lines SW-1573/2R120 and GLC4/ADR is reduced by an energy-dependent drug export mechanism which prevents efficient transport of drug to the target. Since P-glycoprotein expression in lung tumors is generally low, these MDR lung cancer cell lines can be used as a model to study alternative mechanisms leading to multidrug resistance in this tumor type.

Adenosine Triphosphate↗
PubMed1992

Prenatal diagnosis of systemic disorders of the respiratory chain in cultured amniocytes and chorionic villus fibroblasts by studying the formation of lactate and pyruvate from glucose.

Formation of lactate and pyruvate from glucose was studied in cultured amniocytes and chorionic villus fibroblasts from controls, either untreated or treated with azide, an inhibitor of cytochrome c oxidase, or other inhibitors of the mitochondrial respiratory chain. Amniocytes with an established cytochrome c oxidase deficiency were also investigated. Control amniocytes treated with azide as well as cytochrome c oxidase deficient amniocytes displayed strongly increased lactate-to-pyruvate ratios after incubation with glucose, compared to control cells. Elevated lactate-to-pyruvate ratios were also found in chorionic villus fibroblasts in which complexes I, III or IV were inhibited by rotenone, antimycin or azide, respectively. We conclude that measurement of lactate and pyruvate production from glucose in cultured amniocytes and/or chorionic villus fibroblasts allows adequate prenatal diagnosis of systemic cytochrome c oxidase deficiency and presumably of other systemic deficiencies of mitochondrial respiratory chain enzymes.

Amnion↗
PubMed1990

Menadione partially restores NADH-oxidation and ATP-synthesis in complex I deficient fibroblasts.

In this paper we report our studies on the effects of menadione in cultured fibroblasts treated with rotenone to block complex I. A normalization of the lactate to pyruvate ratio after incubation with glucose, an increased production of 14CO2 from [6-14C]glucose and an increased intra-cellular concentration of ATP was observed in the presence of micromolar concentrations of menadione. These results not only demonstrate the potential value of menadione in complex I deficient patients but also suggest that this system can be used advantageously for the in vitro assessment of therapeutic agents for disorders of the mitochondrial respiratory chain.

Adenosine Triphosphate↗
PubMed1990

Establishing special needs car seat loan program.

Car seat loan and rental programs have provided many families with low-cost access to child restraints. When an infant or child is unable to be accommodated in a standard car seat or seat belt owing to physical or medical problems, parents of these children have few, if any available resources. The establishment and operation of a loan program at the Indiana University School of Medicine for children who are medically fragile is reviewed in this article. This program was developed by the Automotive Safety for Children Program at the James Whitcomb Riley Hospital for Children, Indiana University Medical Center, to meet the special transportation needs of children with respiratory, orthopaedic, and other medical and physical difficulties. A summary table is included to highlight restraints that have performed satisfactorily during dynamic crash tests and are used to meet patient transportation needs at Riley Hospital. Guidelines for establishing and maintaining a child restraint loan program for children with special needs are outlined to encourage replication of this effort.

Child↗
PubMed1989

Studies on the formation of lactate and pyruvate from glucose in cultured skin fibroblasts: implications for detection of respiratory chain defects.

We investigated the time course of the formation of lactate and pyruvate from glucose in cultured skin fibroblasts from controls, from a patient with a cytochrome c oxidase deficiency and from controls treated with inhibitors of the individual respiratory chain complexes. Fibroblasts from the patient and inhibitor treated fibroblasts produced more lactate and less pyruvate; this resulted in a significant increase in the lactate to pyruvate ratio, reflecting an increased cytosolic NADH/NAD+ redox state. We conclude that measurement of lactate and pyruvate production from glucose in cultured skin fibroblasts can be of value in the diagnosis of inherited diseases of the mitochondrial respiratory chain.

Cells, Cultured↗
PubMed1987

Treatment of congenital dislocation of the hip. Management before walking age.

Neonatal infants with Ortolani-positive dislocated hips are easily managed by reduction and maintenance of the reduction using a divarication splint, cast, or Pavlik harness. Sixty-six patients with 85 complete, congenitally dislocated hips (Ortolani negative) unassociated with other neuromuscular disorders were examined to assess a method of prereduction traction in the treatment of congenital dislocation of the hip. Forty of the 66 patients were six months of age or younger at the beginning of traction treatment. The remaining 26 were younger than 12 months of age prior to the treatment protocol. Overhead traction with the hip flexed to 90 degrees was employed. Gradual hip abduction to 70 degrees (140 degrees combined abduction) was accomplished over the next ten to 14 days. If the dislocated hip was still in a station above Hilgenreiner's line, then cross traction was applied to add another vector of force to pull the femoral head distally. At an average of 18 days into the treatment protocol, an examination under anesthesia with closed reduction was performed and the patient immobilized in a double hip spica in the "human" position for six to eight weeks. This was followed by use of an Ilfeld divarication splint for nine months. This traction/reduction program was effective in 91% of these cases (60 of 66). Six patients (ten hips) required an open procedure because of persistent instability in spite of reducibility. To date, there is no incidence of avascular necrosis using the criteria of Salter for whole head avascular necrosis and the criteria of Kalamchi and MacEwen for partial head avascular necrosis.

Braces↗
PubMed1986

Lactate dehydrogenase and alkaline phosphatase isoenzymes and protein-bound sialic acid in regenerating rat liver.

Lactate dehydrogenase (LDH) and alkaline phosphatase (AP) isoenzyme patterns and protein-bound sialic acid content were compared between normal, regenerating rat liver 10 days after partial hepatectomy and fetal rat liver. For this purpose, liver from ten adult rats and two pools of ten fetal livers each were examined. Isoenzymes were separated by electrophoresis on cellulose acetate and their percent distribution calculated after quantitation by densitometry of the bands. LDH-5 and LDH-4 combined represented in all the tissues examined 90%-94% of the total activity. LDH-5/LDH-4 ratios were nearly equivalent in the normal and regenerated liver (7.14, 6.41), but substantially lower in fetal liver (2.50). Two bands of AP were visualized in electropherograms. AP-1/AP-2 ratio was lower in regenerated liver (1.57) as compared to normal liver (2.27) and still lower in fetal liver (1.06). Protein-bound sialic acid was, on protein basis, slightly but not significantly higher in regenerated liver (1.71 microgram/mg protein) than in normal liver (1.43), and significantly higher in fetal liver (1.87). The relatively small differences in isoenzyme patterns and in protein-bound sialic acid between regenerated and normal liver as compared to those between fetal and normal tissue add support to the view that the cells in regenerated liver are not of embryonic origin.

Alkaline Phosphatase↗
PubMed1983

Presenile cataracts in phenytoin-treated epileptic patients.

Cataracts developed in two young adults who were receiving prolonged antiepileptic treatment with phenobarbital sodium and phenytoin sodium. The known side effects of these drugs are serious and varied, and phenytoin is strongly implicated in the etiology of cataracts in human beings. Results of our research study on rats supported our view on the cataractogenic action of phenytoin.

Adult↗
PubMed1983

Presenile cataracts in hydantoin-treated epileptic patients.

Two young epileptic adults developed cataracts resembling presenile diabetic lens changes, while on prolonged antiepileptic treatment with phenobarbitone and diphenylhydantoin (DPH). A research study on rats supported our view on the cataractogenic action of DPH.

Adult↗
PubMed1981

Prostaglandin E2 and cyclic AMP in tumor and plasma of breast cancer patients.

Prostaglandin E2 and cyclic AMP (cAMP) levels were measured in tumors and plasma of 78 patients with benign and malignant breast tumors. Two groups of malignant tissues were found, one with a high level of PGE2 (M = 55.4 pg/mg) and one with a low level (M = 10.7 pg/mg). The low level did not differ significantly from the benign tissue level (M = 8.7 pg/mg). Two malignant groups could not be detected in the plasma levels. Plasma PGE2 concentration (in form of the 13,14-dihydro-15-Keto metabolite) did not reflect the tissue levels, and no difference was found between the benign (M = 59.9 pg/ml) and the malignant (M = 62.3 pg/ml) patients, but both concentrations were higher than those of healthy controls (M = 34.4 pg/ml). The stage of the cancer, the histological classification and, most important, the period of survival, could not be related to the differences in the PGE2 tissue levels. Neither could plasma cAMP be nominated as a breast cancer market because no difference was found between the cAMP levels of benign tumor patients (M = 16.48 pmol/ml), of malignant tumor patients (M = 21.14 pmol/ml) and of healthy controls (M = 19.07 pmol/ml). The conclusion is that although high amounts of PGE2 appear in some malignant breast tumors, they do not affect the clinical situation. These results may explain the failure to treat human breast cancer patients with prostaglandin synthetase inhibitors.

Adult↗
PubMed1979

Prostaglandin E2 and cyclic AMP levels in human breast tumors.

Prostaglandin E2 (PGE2) and cyclic adenosine-3', 5'-monophosphate (cAMP) concentrations were measured in human benign and malignant breast tumors by radioimmunoassay. Two groups were found among the malignant tissues, one with high PGE2 (M = 65.89 pg/mg) and high cAMP (M = 0.704 pmole/mg) concentrations and one with low concentrations (M = 9.24 pg/mg and M = 0.299 pmole/mg, respectively). The low PGE2 levels in the malignant tumors did not differ significantly from the levels found in benign tumors (M = 8.06 pg/mg). cAMP levels were positively and highly correlated (r = +0.81) with PGE2 levels. No bone osteolysis could be discovered in any of the patients a few weeks after mastectomy operation, but PGE2 analysis of breast tumors may have prognostic value for the future.

Bone Neoplasms↗
PubMed1978

Crystalline cytoplasmic inclusions in the liver cells of two mongrel dogs.

Crystalline inclusions were found in the cytoplasmic matrix of the liver cells in 2 out of 5 healthy mongrel dogs. The crystals were rectangular, with fine granular structure and free from the surrounding membrane. Their appearance was different from the intramitochondrial crystalline inclusions described in human and dog livers, as well as from those observed in the livers of other species. The significance of this unique finding remains unclear, but it is suggested that these inclusions represent crystalized protein.

Animals↗